肝移植术后应用免疫检查点抑制剂治疗1例并文献复习

Safety and efficacy of immune checkpoint inhibitors therapy in liver transplantation recipients:an analysis report of literature published

目的探讨肝移植(liver transplantation,LT)受者术后再次出现恶性肿瘤后,免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的临床应用及治疗效果。方法回顾性分析青岛大学附属医院收治的1例44岁男性肝移植受者移植术后11个月肿瘤复发并接受ICIs治疗的临床资料。以"肝移植""免疫检查点抑制剂""排斥反应"和"liver transplantation OR LT""immune checkpoint inhibitors OR ICIs""rejection reaction"为中英文关键词,检索中国知网(CNKI)、万方数据库(WanFang)、维普数据库(VIP)、中华医学期刊全文数据库、PubMed、EMBASE、Web of Science及Google scholar等中外文数据库中有关肝移植受者出现恶性肿瘤后接受ICIs治疗的文献报道并予以分析。检索时间从数据库建立至2021年12月31日。分析肝移植受者术后出现恶性肿瘤使用ICIs治疗后疾病应答、不良反应及预后情况。结果本例受者经肝穿刺活检证实为慢性排斥反应合并药物性肝损伤,经间断行双重血浆分子吸附系统联合血浆置换及抗排斥反应等治疗后,最终于术后37个月死于肿瘤复发。经检索,本研究最终纳入28篇文献,共47例受者。其中,男性37例,女性10例;中位年龄57(14~71)岁。移植术后发生肝细胞肝癌28例(59.6%),恶性黑色素瘤11例(23.4%),非小细胞肺癌3例(6.4%),结直肠癌、胆管细胞癌、鳞状细胞癌、咽下鳞状细胞癌及移植后淋巴细胞增殖性疾病各1例(2.1%)。单用PD-1单抗治疗者42例,其中单用纳武利尤单抗(Nivolumab)者23例,单用帕博利珠单抗(Pembrolizumab)者11例,单用卡瑞利珠单抗(Camrelizumab)者3例,单用特瑞普利单抗(Toripalimab)者5例;单用CTLA-4单抗治疗者3例,均采用依匹木单抗(Ipilimumab)3例;采用Pembrolizumab+Ipilimumab联合方案治疗者2例。随访时间为37.9(20.5~84.7)个月。ICIs治疗的总体缓解率为29.8%(14/47),疾病进展率为68.1%(32/47);有31.9%(15/47)的受者发生了排斥反应,病死率为61.7%(29/47),中位生存时间为6.5(0.3~48.0)个月。结论目前肝移植术后出现恶性肿瘤受者使用ICIs治疗后的移植物排斥反应发生率及病死率均较高,此类受者应慎重考虑ICIs治疗。

Objective To explore the clinical applications and therapeutic outcomes of immune checkpoint inhibitors(ICIs)on liver transplantation(LT)recipients after tumor development.Methods Eight databases including PubMed,China National Knowledge Infrastructure,Wanfang Data,CQVIP,PubMed,EMBASE,Web of Science and Google scholar were accessed for searching the relevant literature articles in both Chinese and English from the establishment of databases to December 31,2021.Disease response,adverse reactions and prognoses of patients with malignant tumors after LT and receiving ICIs were analyzed.Results The patient was diagnosed as chronic rejection plus drug-induced liver injury by liver biopsy.After intermittent treatment with DPMAS plus plasma exchange and immunosuppressants,he finally died of tumor recurrence at 37 months after LT.After screening,a total of 28 articles on the application of ICIs after LT were retrieved.In these articles,there were 47 patients(37 males and 10 females)with a median age of 57(14-71)years and the predominant type of tumor after LT was hepatocellular carcinoma(28/47,59.6%),followed by malignant melanoma in 11 cases(23.4%),non-small cell lung cancer in 3 cases(6.4%),colorectal cancer,cholangiocarcinoma,squamous cell carcinoma,hypopharyngeal squamous cell carcinoma and post transplant lymphoproliferative disease(PTLD)in 1 case(2.1%).The overall remission rate after ICI treatment was 29.8%(14/47)and the disease progression rate 68.1%(32/47).Among them,31.9%(15/47)had immune rejection.Case fatality rate was 61.7%(29/47)and median survival time 6.5(0.3-48.0)months.Conclusions Depending on existing publications,among those LT recipients with malignant tumors treated by ICIs,the rate of graft rejection and patient mortality are higher.ICIs should be carefully considered for LT patients and further researches are required.